NM_000552.5:c.4883T>C

Variant names:

• chr12-6018535-A-G
• rs61750584
• NM_000552.5:c.4883T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS4 PP1_Moderate PS3_Supporting PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.4883T>C is a missense variant in VWF predicted to cause substitution of isoleucine by threonine at amino acid 1628. The Grpmax filtering allele frequency in gnomAD v4.1 is 2.800e-7 (based on 2/1179884 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 for (PM2_Supporting). The computational predictor REVEL gives a score of 0.703, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least sixteen patients with this variant have been diagnosed with VWD Type 2A, of whom nine are documented to have displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (measured by VWF:RCo) low VWF:RCo/ VWF:Ag ratio, and absence of high-molecular weight VWF multimers, which together are highly specific for VWD type 2A (PP4_Moderate, PMID:28536718, VCEP member-provided data). Thirteen total probands have been described in sufficient detail to establish a phenotype specific to VWD type 2A (PS4_VeryStrong, PMID:28536718, VCEP member-provided data, PMID:28971901). The variant has been reported to segregate with VWD type 2A through 6 affected meioses from 1 family and 3 affected meioses in another (PP1_Moderate; PMID:1673047, PMID:28971901). Proteolysis assays of an exogenously expressed VWF fragment showed higher susceptibility of the variant protein to ADAMTS13 proteolysis under non-denaturing conditions (PMID:16221672, PMID:16322474, PMID:23110044), indicating that this variant has a damaging effect on protein function (PS3_Supporting). The variant protein exhibited normal multimer distribution (PMID:16322474) and secretion rate (PMID:8123844) in vitro. In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3_supporting, PS4, PP1_Moderate, PM2_Supporting, PP3, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114115/MONDO:0015628/081

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14 U:1 O:1
• Conservation: PhyloP100: 7.30
• Publications: 15 publications found

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

VWF Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.4883T>C	p.Ile1628Thr	missense	Exon 28 of 52	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.4883T>C	p.Ile1628Thr	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.4883T>C	p.Ile1628Thr	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+10807T>C		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461722 Hom.: 0 Cov.: 40 AF XY: 0.00000275 AC XY: 2 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111896

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary von Willebrand disease (3)
3	-	-	not provided (4)
3	-	-	von Willebrand disease type 2 (3)
3	-	-	Von Willebrand disease type 2A (3)
-	1	-	von Willebrand disease type 1 (1)
1	-	-	von Willebrand disorder (1)
1	-	-	VWF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.88	N
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.27	B
Vest4		0.83
MutPred		0.79		Gain of catalytic residue at V1630 (P = 5e-04)
MVP		0.90
MPC		0.34
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.98
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61750584; hg19: chr12-6127701;